Hyperadrenergic and neuropathic features based on clinical autonomic testing in individuals with POTS: an observational cross-sectional study

Hyperadrenergic and neuropathic features have been described in postural tachycardia syndrome (POTS). This study describes the prevalence, autonomic testing characteristics, and symptom severity of individuals with hyperadrenergic and neuropathic features in a laboratory-diagnosed POTS cohort. We performed a cross-sectional study of individuals with a laboratory diagnosis of POTS. Hyperadrenergic POTS (HyperPOTS) features were defined as an upright norepinephrine level of > 600 pg/mL and/or > 3 times their respective supine norepinephrine. Neuropathic POTS (NeuroPOTS) features were defined by a CASS ≥ 2 and/or ≥ 1 sudomotor abnormalities. Autonomic symptom severity was determined by the Composite Autonomic Symptom Score (COMPASS-31). Other standard autonomic reflex testing components, including heart rate response to deep breathing (HRDB), Valsalva, and 10-min head-up tilt testing, were also performed. Of the 223 participants (mean age 31.6 years; female 89%), 161 (41%) had HyperPOTS features, 113 (29%) exhibited NeuroPOTS features, and 40 (18%)/48 (22%) demonstrated neither or both, respectively. NeuroPOTS features were associated with higher supine HR and rates of abnormal HRDB than those without NeuroPOTS. No significant differences in COMPASS-31 scores were found between all groups studied. HyperPOTS and NeuroPOTS are common, co-occurring features in adults with POTS. Autonomic symptom burden did not differ significantly between phenotypes, likely reflecting insensitivity of the COMPASS-31 to phenotype-specific domains. NeuroPOTS was associated with impaired cardiovagal function, consistent with involvement in cardiac postganglionic parasympathetic pathways, though this is partly confounded by HRDB's inclusion in our NeuroPOTS definition. These findings support the concept that POTS phenotyping may aid in therapy selection, and the need for phenotype-sensitive symptom instruments.